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J. Exp. Clin. Cancer Res., Jan 28 2025, 44 (1) 28 | https://doi.org/10.1186/s13046-024-03247-w
Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD
Jongbok Lee1,2, Hyeonjeong Kang1,3, Branson Chen1, Yoosu Na1, Ismat Khatri1, Fraser Soares4, Housheng Hansen He4,5, Arjun D. Law4, Tianzhong Pan6,7, Armin Gerbitz4, Xiaoyu Zhu6,7, Mark D. Minden4 and Li Zhang1,3,8*
1Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
2Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
4Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
5Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
6Department of Hematology, the First Afliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
7Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
8Department of Immunology, University of Toronto, Toronto, ON, Canada.
*Correspondence: Li Zhang
1Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
2Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
4Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
5Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
6Department of Hematology, the First Afliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
7Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
8Department of Immunology, University of Toronto, Toronto, ON, Canada.
*Correspondence: Li Zhang
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a second-line treatment with curative potential for leukemia patients. However, the prognosis of allo-HSCT patients with disease relapse or graft-versus-host disease (GvHD) is poor. CD4+ or CD8+ conventional T (Tconv) cells are critically involved in mediating anti-leukemic immune responses to prevent relapse and detrimental GvHD. Hence, treatment for one increases the risk of the other. Thus, therapeutic strategies that can address relapse and GvHD are considered the Holy Grail of allo-HSCT. CD3+CD4-CD8- double-negative T cells (DNTs) are unconventional mature T cells with potent anti-leukemia effects with "off-the-shelf" potential. A phase I clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy for patients with relapsing acute myeloid leukemia (AML) post-allo-HSCT. Here, we studied the impact of DNTs on the anti-leukemic and GvHD-inducing activities of Tconv cells. DNTs synergized with Tconv cells to mediate superior anti-leukemic activity. Mechanistically, DNTs released soluble factors which activated and evoked potent anti-leukemic activities of Tconv cells. In contrast, DNTs suppressed GvHD-inducing activities of Tconv cells in a CD18-dependent manner by mediating cytotoxicity against proliferative Tconv cells. The seemingly opposite immunological activities of DNTs were dictated by the presence or absence of AML cells. Collectively, these results support the potential of DNTs as an adjuvant to allo-HSCT to address both disease relapse and GvHD.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-02-10)
- 국외 연구진
- 의약학 > 면역의학
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